Sarcopenia in colorectal cancer is related to socio-economic deprivation and Body Mass Index alone misrepresents underlying muscle loss in the deprived.

BACKGROUND & AIMS: Patients with colorectal cancer who are more socio-economically deprived have worse outcomes; deprivation is also associated with higher obesity rates, defined as a body mass index (BMI) of greater than thirty. Body composition (BC) factors such as sarcopenia and myosteatosis are also known to predispose to poorer outcomes following colorectal cancer surgery. There is limited evidence to date to relate the effect of deprivation upon these host characteristics that are linked to prognosis. We aimed to examine the relationship between deprivation and body composition in colorectal cancer. METHODS: Analysis was performed on a prospectively collected database of preoperative primary colorectal cancer patients at St Mark's - The National Bowel Hospital, UK. Body composition characteristics were identified by analysing the L3 axial slices of Computer Tomogram (CT) slices of preoperative staging using Slice-O-Matic software with Automatic Body composition Analyser using Computed tomography image Segmentation (ABACS) L3 plug-in. Deprivation status for each patient was determined using their postal code which was linked to the Index of Multiple Deprivation (IMD). Each domain of the IMD was examined individually in relation to BC characteristics. Binary logistic regression analysis was performed on the data using a model developed from previous published analyses of this dataset. RESULTS: Four hundred and nineteen patients were included in the final analysis, the median age was 69 years and 57% of the patient population was male. Patients who were more deprived were significantly more likely to be sarcopenic [OR 1.56 (95% CI 1.01-2.41, p = 0.045)] and myosteatotic [OR 1.69 (95% CI 1.019-2.81, p = 0.042)]. More deprived patients were also more likely to have a lower BMI [OR 0.60 (95% CI 0.38-0.94, p = 0.026)] despite no significant difference in visceral obesity between the most and least deprived. CONCLUSIONS: Deprivation is an important independent determinant of sarcopenia in the colorectal cancer population. Identifying these patients early and addressing reversible factors may help improve post-operative surgical outcomes in this poor prognostic group. Sarcopenia may be a premorbid state in the deprived colorectal cancer patient that may not be wholly driven by tumour characteristics.

Sarcopenia is independently associated with poor preoperative physical fitness in patients undergoing colorectal cancer surgery.

BACKGROUND: Accurate preoperative risk assessment for major colorectal cancer (CRC) surgery remains challenging. Body composition (BC) and cardiopulmonary exercise testing (CPET) can be used to evaluate risk. The relationship between BC and CPET in patients undergoing curative CRC surgery is unclear. METHODS: Consecutive patients undergoing CPET prior to CRC surgery between 2010 and 2020 were identified between two different UK hospitals. Body composition phenotypes such as sarcopenia, myosteatosis, and visceral obesity were defined using widely accepted thresholds using preoperative single axial slice CT image at L3 vertebrae. Relationships between clinicopathological, BC, and CPET variables were investigated using linear regression analysis. RESULTS: Two hundred eighteen patients with stage I-III CRC were included. The prevalence of sarcopenia, myosteatosis, and visceral obesity was 62%, 33%, and 64%, respectively. The median oxygen uptake at anaerobic threshold (VO2 at AT) was 12.2 mL/kg/min (IQR 10.6-14.2), and oxygen uptake at peak exercise (VO2 peak) was 18.8 mL/kg/min (IQR 15.4-23). On univariate linear regression analysis, male sex (P < 0.001) was positively associated with VO2 at AT. While ASA grade (P < 0.001) and BMI (P = 0.007) were negatively associated with VO2 at AT, on multivariate linear regression analysis, these variables remained significant (P < 0.05). On univariate linear regression analysis, male sex (P < 0.001) was positively associated with VO2 peak, whereas age (P < 0.001), ASA grade (P < 0.001), BMI (P = 0.003), sarcopenia (P = 0.015), and myosteatosis (P < 0.001) were negatively associated with VO2 peak. On multivariate linear regression analysis age (P < 0.001), ASA grade (P < 0.001), BMI (P < 0.001), and sarcopenia (P = 0.006) were independently and negatively associated with VO2 peak. CONCLUSIONS: The novel finding that sarcopenia is independently associated with reduced VO2 peak performance in CPET supports the supposition that reduced muscle mass relates to poor physical function in CRC patients. Further work should be undertaken to assess whether sarcopenia diagnosed on CT can act as suitable surrogate for CPET to further enhance personalized risk stratification.

A systematic review of automated segmentation of 3D computed-tomography scans for volumetric body composition analysis.

Automated computed tomography (CT) scan segmentation (labelling of pixels according to tissue type) is now possible. This technique is being adapted to achieve three-dimensional (3D) segmentation of CT scans, opposed to single L3-slice alone. This systematic review evaluates feasibility and accuracy of automated segmentation of 3D CT scans for volumetric body composition (BC) analysis, as well as current limitations and pitfalls clinicians and researchers should be aware of. OVID Medline, Embase and grey literature databases up to October 2021 were searched. Original studies investigating automated skeletal muscle, visceral and subcutaneous AT segmentation from CT were included. Seven of the 92 studies met inclusion criteria. Variation existed in expertise and numbers of humans performing ground-truth segmentations used to train algorithms. There was heterogeneity in patient characteristics, pathology and CT phases that segmentation algorithms were developed upon. Reporting of anatomical CT coverage varied, with confusing terminology. Six studies covered volumetric regional slabs rather than the whole body. One study stated the use of whole-body CT, but it was not clear whether this truly meant head-to-fingertip-to-toe. Two studies used conventional computer algorithms. The latter five used deep learning (DL), an artificial intelligence technique where algorithms are similarly organized to brain neuronal pathways. Six of seven reported excellent segmentation performance (Dice similarity coefficients > 0.9 per tissue). Internal testing on unseen scans was performed for only four of seven algorithms, whilst only three were tested externally. Trained DL algorithms achieved full CT segmentation in 12 to 75 s versus 25 min for non-DL techniques. DL enables opportunistic, rapid and automated volumetric BC analysis of CT performed for clinical indications. However, most CT scans do not cover head-to-fingertip-to-toe; further research must validate using common CT regions to estimate true whole-body BC, with direct comparison to single lumbar slice. Due to successes of DL, we expect progressive numbers of algorithms to materialize in addition to the seven discussed in this paper. Researchers and clinicians in the field of BC must therefore be aware of pitfalls. High Dice similarity coefficients do not inform the degree to which BC tissues may be under- or overestimated and nor does it inform on algorithm precision. Consensus is needed to define accuracy and precision standards for ground-truth labelling. Creation of a large international, multicentre common CT dataset with BC ground-truth labels from multiple experts could be a robust solution.

A systematic review of the pathological determinants of outcome following resection by pelvic exenteration of locally advanced and locally recurrent rectal cancer.

BACKGROUND: Despite multimodal therapy 5-15% of patients who undergo resection for advanced rectal cancer (LARC) will develop local recurrence. Management of locally recurrent rectal cancer (LRRC) presents a significant therapeutic challenge and even with modern exenterative surgery, 5-year survival rates are poor at 25-50%. High rates of local and systemic recurrence in this cohort are reflective of the likely biological aggressiveness of these tumour types. This review aims to appraise the current literature identifying pathological factors associated with survival and tumour recurrence in patients undergoing exenterative surgery. METHODS: A systematic review was carried out searching MEDLINE, EMBASE and COCHRANE Trials database for all studies assessing pathological factors influencing survival following pelvic exenteration for LARC or LRRC from 2010 to July 2021 following PRISMA guidelines. Risk of bias was assessed using QUIPS tool. RESULTS: Nine cohort studies met inclusion criteria, reporting outcomes for 2864 patients. Meta-analysis was not possible due to significant heterogeneity of reported outcomes. Resection margin status and nodal disease were the most commonly reported factors. A positive resection margin was demonstrated to be a negative prognostic marker in six studies. Involved lymph nodes and lymphovascular invasion also appear to be negative prognostic markers with tumour stage to be of lesser importance. No studies assessed other adverse tumour features that would not otherwise be included in a standard histopathology report. CONCLUSION: Pathological resection margin status is widely demonstrated to influence disease free and overall survival following pelvic exenteration for rectal cancer. With increasing R0 rates, other adverse tumour features must be explored to help elucidate differences in survival and potentially guide tailored oncological treatment.

Tumour grade and stage are associated with specific body composition phenotypes with visceral obesity predisposing the host to a less aggressive tumour in colorectal cancer.

BACKGROUND: Sarcopenia, myosteatosis and visceral obesity (VO) are known to negatively impact on outcomes from colorectal cancer (CRC). Little is known about tumour factors associated with these body composition (BC) phenotypes. We aimed to identify whether histopathological tumour characteristics were associated with various BC phenotypes. METHODS: A prospectively collected database of patients undergoing surgery for primary CRC at a tertiary referral unit in the United Kingdom was analysed. Sarcopenia, myosteatosis and VO were identified on preoperative CT. Binary logistic regression modelling was performed to determine significant associations between tumour stage, grade and BC phenotype. RESULTS: Final analysis included 795 patients; median age 69, 56% male, 65% were sarcopenic, 72% myosteatotic, 52% VO and 20% had sarcopenic obesity (SO). VO patients were significantly less likely to have advanced T Stage (T3-4) OR0.62(95%CI 0.44-0.86, p = 0.005); nodal metastases OR0.60(95%CI 0.44-0.82, p = 0.001); vascular invasion OR0.63(95%CI 0.46-0.88, p = 0.006) and poor tumour differentiation OR0.49(95%CI 0.28-0.86, p = 0.012). Myosteatotic patients were more likely to have metastatic disease OR2.31(95%CI 1.15-4.63, p = 0.018) but less likely to have poorly differentiated tumours OR0.48(95%CI 0.27-0.86, p = 0.013). SO patients were significantly more likely to have poorly differentiated tumours OR2.01(95%CI 1.04-3.87, p = 0.037). CONCLUSION: VO predisposes to earlier stage tumours with a less aggressive tumour phenotype. The SO group have adverse tumour characteristics which may be explained by differences in fat distribution. Myosteatosis relates to increased likelihood of distant metastasis that may be related to a systemic inflammatory response, despite the association with better differentiated tumours.

Empty pelvis syndrome: a systematic review of reconstruction techniques and their associated complications.

AIM: Empty pelvis syndrome is a major contributor to morbidity following pelvic exenteration. Several techniques for filling the pelvis have been proposed; however, there is no consensus on the best approach. We evaluated and compared the complications associated with each reconstruction technique with the aim of determining which is associated with the lowest incidence of complications related to the empty pelvis. METHOD: The systematic review protocol was prospectively registered with PROSPERO (CRD42021239307). PRISMA-P guidelines were used to present the literature. PubMed and MEDLINE were systematically searched up to 1 February 2021. A dataset containing predetermined primary and secondary outcomes was extracted. RESULTS: Eighteen studies fulfilled our criteria; these included 375 patients with mainly rectal and gynaecological cancer. Only three studies had a follow-up greater than 2 years. Six surgical interventions were identified. Mesh reconstruction and breast prosthesis were associated with low rates of small bowel obstruction (SBO), entero-cutaneous fistulas and perineal hernia. Findings for myocutaneous flaps were similar; however, they were associated with high rates of perineal wound complications. Omentoplasty was found to have a high perineal wound infection rate (40%). Obstetric balloons were found to have the highest rates of perineal wound dehiscence and SBO. Silicone expanders effectively kept small bowel out of the pelvis, although rates of pelvic collections remained high (20%). CONCLUSION: The morbidity associated with an empty pelvis remains considerable. Given the low quality of the evidence with small patient numbers, strong conclusions in favour of a certain technique and comparison of these interventions remains challenging.

BiCyCLE NMES-neuromuscular electrical stimulation in the perioperative treatment of sarcopenia and myosteatosis in advanced rectal cancer patients: design and methodology of a phase II randomised controlled trial.

BACKGROUND: Colorectal cancer is associated with secondary sarcopenia (muscle loss) and myosteatosis (fatty infiltration of muscle) and patients who exhibit these host characteristics have poorer outcomes following surgery. Furthermore, patients, who undergo curative advanced rectal cancer surgery such as pelvic exenteration, are at risk of skeletal muscle loss due to immobility, malnutrition and a post-surgical catabolic state. Neuromuscular electrical stimulation (NMES) may be a feasible adjunctive treatment to help ameliorate these adverse side-effects. Hence, the purpose of this study is to investigate NMES as an adjunctive pre- and post-operative treatment for rectal cancer patients in the radical pelvic surgery setting and to provide early indicative evidence of efficacy in relation to key health outcomes. METHOD: In a phase II, double-blind, randomised controlled study, 58 patients will be recruited and randomised (1:1) to either a treatment (NMES plus standard care) or placebo (sham-NMES plus standard care) group. The intervention will begin 2 weeks pre-operatively and continue for 8 weeks after exenterative surgery. The primary outcome will be change in mean skeletal muscle attenuation, a surrogate marker of myosteatosis. Sarcopenia, quality of life, inflammatory status and cancer specific outcomes will also be assessed. DISCUSSION: This phase II randomised controlled trial will provide important preliminary evidence of the potential for this adjunctive treatment. It will provide guidance on subsequent development of phase 3 studies on the clinical benefit of NMES for rectal cancer patients in the radical pelvic surgery setting. TRIAL REGISTRATION: Protocol version 6.0; 05/06/20. ClinicalTrials.gov NCT04065984 . Registered on 22 August 2019; recruiting.

Vascular calcification and response to neoadjuvant therapy in locally advanced rectal cancer: an exploratory study.

PURPOSE: Patients with locally advanced rectal cancer (LARC) may experience a clinical complete response (cCR) to neoadjuvant chemoradiotherapy (NACRT) and opt for non-operative management. Pathological factors that relate to NACRT response have been well described. Host factors associated with response, however, are poorly defined. Calcification of the aortoiliac (AC) vessels supplying the rectum may influence treatment response. METHODS: Patients with LARC having NACRT prior to curative surgery at Glasgow Royal Infirmary (GRI) and St Mark's hospital (SMH) between 2008 and 2016 were identified. AC was scored on pre-treatment CT imaging. NACRT response was assessed using pathologic complete response (pCR) rates, tumour regression grades (TRGs), the NeoAdjuvant Rectal score and T-/N-downstaging. Associations were assessed using Chi-squared, Mantel-Haenszel and Fisher's exact tests. RESULTS: Of 231 patients from GRI, 79 (34%) underwent NACRT for LARC. Most were male (58%), aged over 65 (51%) with mid- to upper rectal tumours (56%) and clinical T3/4 (95%), node-positive (77%) disease. pCR occurred in 10 patients (13%). Trends were noted between higher clinical T stage and poor response by Royal College of Pathologist's TRG (p = 0.021) and tumour height > 5 cm and poor response by Mandard TRG (0.068). In the SMH cohort, 49 of 333 (15%) patients underwent NACRT; 8 (16%) developed a pCR. AC was not associated with NACRT response in either cohort. CONCLUSIONS: AC was not associated with NACRT response in this cohort. Larger contemporary cohorts are required to better assess host determinants of NACRT response and develop predictive models to improve patient selection.

Challenging the Current Risk Factors of Appendiceal Neuroendocrine Neoplasms: Can They Accurately Predict Local Lymph Nodal Invasion? Results from a Large Case Series.

BACKGROUND: Appendiceal neuroendocrine neoplasms (ANEN) are uncommon entities, which run mostly an indolent course. Appendicectomy alone is usually curative, except for in a selected group of patients that are deemed to be at risk of loco-regional metastases, in whom a completion right hemicolectomy (RHC) is recommended. The current "Guidelines" criteria for the latter have been controversial, and may result in overtreatment, which is concerning for a young patient population. OBJECTIVE: The aim of this study is to evaluate the prognostic value of the current criteria in identifying more accurately those at-risk patients. METHODS: This was a retrospective study of the 263 cases of ANEN referred for advice or management to a tertiary referral unit over a 10-year period. Seventy-two patients underwent RHC, based on criteria, suggested by International Guidelines. Each one of those was assessed to identify whether it correlated with lymph node invasion (LNI) at the RHC surgical specimen. RESULTS: Tumour grade (p < 0.001), vascular (p = 0.044) and lymph vessel invasion (p < 0.001) were all found to be statistically significant independent risk factors for LNI identified following RHC, whilst tumour size (p = 0.375) and mesoappendiceal invasion (MAI) (p = 0.317) were not statistically significant. However, deep MAI and tumour size >2 cm showed a correlation with each other on LNI positive subgroup analysis. Location in appendiceal base made LNI more likely but again was not significant (p = 0.133). CONCLUSIONS: Higher tumour grade and lymphovascular invasion should be considered as the most important risk prognosticators. Surprisingly, tumour size was not found to be significant in our cohort. Further international multicentre studies with large numbers of patients are needed to fully validate those data.